Catalyst- and Additive-Free Synthesis of Fluoroalkoxyquinolines

Abstract

A nucleophilic substitution approach has been developed for the synthesis of C4 fluoroalkoxyquinolines from 4-haloquinolines by utilizing hexafluoro-2-propanol and trifluoroethanol as nucleophiles. The method is also applicable for 2-chloroquinolines, 1-chloroisoquinoline, and 2-chlorobenzimidazole. Control experiments revealed that substitution occurs only at the C2 and C4 positions of quinolines.

Quinoline structures are important motifs in natural products and pharmaceutical industries, and they are well known for their various bioactivities.[1] Substitution with fluorine increases lipophilicity,[2] bioavailability,[3] and metabolic stability[4] of organic compounds including quinolines. Therefore, the introduction of a fluorine atom or fluorinated group such as CF₃ on quinoline compounds or other target organic molecules containing a quinoline moiety is the subject of interest for many chemists. Moreover, quinoline derivatives containing fluorine atoms or other fluorinated groups possess important biological activities, including well-known drugs such as ciprofloxacin and 5-fluoroprimaquine (Figure [1]).[5]

In the last two decades, different methods have been developed for the synthesis of fluorine-containing quinoline derivatives. In 2014, the Larionov group introduced fluo­rinated groups at the C2 position of quinoline using perfluoroalkyl- and perfluoroarylsilanes.[6] Fang and Gua developed a protocol for the synthesis of fluorinated quinoline compounds with polyfluoroalcohols.[7] These methods lead to regioselectively C2 fluorinated quinolines via direct C–H functionalization.

In contrast, the C4 position of the quinoline moiety is less readily accessible for direct C–H functionalization.[8] Consequently, very few methods have been reported in which a fluorine atom has been introduced at the C4 position of quinoline. 4-Haloquinolines are utilized extensively for the synthesis of such types of derivatives through the use of palladium catalyst with tetrakis(2,2,2-trifluoroethyl) borate salt as a fluorine source (Scheme [1]).[9] In 2015, the Ritter group also reported the synthesis of C4 fluorinated quinolines from cross-coupling of phenols and alcohols by using phenofluor.[10] Hexafluoro-2-propanol (HFIP) as a solvent has been explored in various C–H functionalization methods[11] and it has also recently been used as a source of fluorinating reagent to couple with quinoline C2 position through C–H functionalization.[7] The synthesis of C4 fluoroalkoxy quinoline from 4-haloquinoline and HFIP has not been explored much.[12] Herein, we report the selective C4-fluoroalkoxylation of halo quinoline with HFIP through nucleophilic substitution of halogens (Cl, Br, I) at the C4 and C2 position of quinolines.

In an optimization study, 4-chloroquinoline was taken as the model substrate and reacted with fluorinated alcohols such as trifluoroethanol (TFE) and HFIP under thermal conditions.

Fortunately, reaction with HFIP (1.0 M) gave the desired product in good yield (Table [1], entry 1). The product was characterized based on 1D NMR spectroscopic and mass spectrometric analyses. Upon varying the amount of HFIP (entries 1–4, Table 1) and best results were obtained by using 0.5 M 4-haloquinoline in HFIP (entry 2, Table 1). Less satisfactory results were obtained at lower reaction temperature (entries 5 and 6, Table 1).

Table 1 Optimization Study

Entry	HFIP (M)	Temp (°C)	Time (h)	Yield of 3a (%)a
1	1.00	120	24	60
2	0.50	120	24	94 (90)b
3	0.33	120	24	85
4	0.25	120	24	73
5	0.50	100	24	90
6	0.50	80	24	45

^a Determined by ¹H NMR analysis of the crude reaction mixture using TCE as internal standard.

^b Isolated yield in parentheses.

After optimization, the substrate scope of the reaction was studied with a range of 4-haloquinolines (Scheme [2]). 4-Bromoquinoline afforded the desired product (3a) with excellent yield even at 100 °C. 2-Trifluoromethyl-4-chloroquinoline (1b) failed to react under current reaction conditions. 2-Aminoarylated and 2-arylated 4-chloroquinoline provided a low yield (30–36%) of the desired product 3c–d. Substitution at the arene ring of quinoline with 6-Me, 6-F, 6-Cl, 6-Br, 7-CF₃, 7-Cl, and 6,7-dimethoxy substituents did not alter the outcome of the reaction and furnished good to excellent yield (55–99%) of C4-fluorinated quinolines 3e–k. 4-Iodo-7-chloroquinoline (1j) was also well-tolerated and gave the fluorinated product in 90% yield at 100 °C. 2-Methyl-4,6-dichloroquinoline also afforded excellent yield of the desired product 3l. The polyaromatic heterocycle 9-chloroacridine reacted successfully to afford the corresponding product 3m in 60% yield (Scheme [2]).

Trifluoroethanol in the presence of base (pyridine) also provided the desired product 4a in 95% yield (Scheme [3]). In this case, a base is necessary for generating nucleophile by abstracting a proton from the OH group of TFE.

Next, quinolines with halogen (Cl, Br, I) substituent at C3, C5, C6, C7, and C8 positions also reacted with HFIP under the standard reaction conditions. All these substrates remained unchanged, and no nucleophilic substitution was observed (Scheme [4]). In contrast, C2 haloquinolines reacted with HFIP to provide the corresponding product (Scheme [5]).

2-Chloroquinoline provided 71% yield of fluoroalkoxy product 6a with HFIP. 2-Chloro-3-benzaldehyde reacted successfully and gave the desired product 6b in low yield. In the case of 2,4-dichloroquinoline, nucleophilic substitution was observed at the C2 position to afford the corresponding fluorinated quinoline 6c in 54% yield. Unfortunately, this methodology is not suitable for use with either 2-chloropyridine or 2-chloropyrimidine (Scheme [5]).

Other heterocyclic compounds containing halogen were also investigated under the standard reaction conditions. 1-Chlorisoquinolines and 2-chlorobenzimidazole (Scheme [6]) were successfully converted into the desired product with low to excellent yield.

4-Halogenated quinoline N-oxide and benzoyl (quinoline-1-ium-1yl)amide failed to react under the developed reaction conditions (Scheme [7]).

The current reaction likely proceeds through nucleo­philic substitution as depicted in Scheme [8].[13] Halogen with –I effect tend to decrease the electron density at the C4 position, resulting in partial positive charge on C4. As a result, the C4 position undergoes ipso-attack from a nucleophile generated from HFIP to give intermediate I, which undergoes rearomatization with the removal of halogen to provide the product.

In summary, we have prepared new derivatives of C4-functionalized quinolines containing fluorinated groups, which are less accessible by the direct C–H activation method. The method has good substrate scope and proceeds with good to excellent yield. A selection of other heterocyclic compounds were also investigated under the standard reaction conditions.

Reagent Information

Unless otherwise stated, all reactions were carried out under air atmosphere in screw-cap reaction vials. All solvents were purchased from Sigma–Aldrich and TCI in sure-seal bottles and used as such. All chemicals were purchased from Sigma Aldrich, Alfa–Aesar, and TCI and used as such. For column chromatography, silica gel (230–400 mesh) procured from Merck was used. A gradient elution using n-hexane and EtOAc was performed with Merck aluminum TLC sheets (silica gel 60F₂₅₄).

Analytical Information

Melting points were recorded with a Bronsted Electro thermal 9100 and Labindia visual melting range. All isolated compounds are characterized by ¹H NMR, ¹³C NMR, ¹⁹F, IR, and HRMS. Mass spectra were recorded with a Waters Q–ToF–Micromass, and NMR spectra were recorded with a Bruker–Avance 600 MHz instrument. IR spectra were recorded with a Shimadzu IRAffinity-1S with a ZnSe single reflection ATR accessory. All ¹H NMR experiments are reported in parts per million (ppm) and were measured relative to the signals for residual chloroform (δ = 7.26 ppm) and CD₃OD-d ₄ (δ = 3.31 ppm) in deuterated solvents. All ¹³C{¹H} NMR spectra are reported in ppm relative to deuterated chloroform (δ = 77.16 ppm) and CD₃OD-d ₄ (δ = 49.0 ppm); all were obtained with ¹H decoupling. All ¹⁹F NMR experiments are reported in parts per million (ppm) from the residual solvent peak. Optimization studies were based on analysis of the crude reaction mixtures with ¹H NMR spectroscopy. NMR yields were calculated by using TCE as an internal standard.

Synthesis of 4-Fluoroalkoxyquinolines; General Procedure

In a reaction vial equipped with a magnetic stir bar, 4-haloquinoline 1a (0.2 mmol) in HFIP (400 μL, 0.5 molar solution) was added. The reaction mixture was stirred at 120 °C (in case of 4-chloroquinoline) or at 100 °C (in case of 4-bromo- or 4-iodoquinoline) for 24 h on a heating mantle. After 24 h, the reaction was cooled to r.t., and the organic solvents were removed under reduced pressure. The residue was then diluted with a saturated solution of NaHCO₃ to neutralize the reaction mixture. The neutralized solution was extracted with EtOAc and collected in a round-bottom flask for further purification. The organic solvent-containing mixture was purified by column chromatography on silica gel (mesh 230–400) to give the desired product. Eluting solvents for chromatography are indicated under the specific compound headings.

Synthesis of 4-(2,2,2-Trifluoroethoxy)quinoline (4a); Typical Procedure

In a reaction vial equipped with a magnetic stir bar, 4-chloroquinoline 1a (0.2 mmol) in TFE (400 μL, 0.5 molar solution) was added. Pyridine (16.8 μL) was then added to the solution of 4a in TFE and the reaction mixture was stirred at 120 °C for 24 h on a heating mantle. After 24 h, the mixture was cooled to r.t., and the organic solvents were removed under reduced pressure. The residue was then diluted with a saturated solution of NaHCO₃ to neutralize the reaction mixture. The neutralized solution was extracted with EtOAc and collected in a round-bottom flask for purification. The organic solvent containing mixture was purified by column chromatography on silica gel (mesh 230–400) to give the desired product. Eluting solvents for chromatography are indicated under the specific compound headings.

Synthesis of 2-Fluoroalkoxyquinolines; General Procedure

In a reaction vial equipped with a magnetic stir bar, 2-chloroquinoline 5a (0.2 mmol) in HFIP (400 μL, 0.5 molar solution) was added. The reaction mixture was then stirred at 120 °C for 24 h on a heating mantle. After 24 h, the reaction was cooled to r.t., and the organic solvents were removed under reduced pressure. The residue was then diluted with a saturated solution of NaHCO₃ to neutralize the reaction mixture. The neutralized solution was extracted with EtOAc and collected in a round-bottom flask for the purification process. The organic solvent containing mixture was purified by column chromatography on silica gel (mesh 230–400) to give the desired product. Eluting solvents for chromatography are indicated under the specific compound headings.

Synthesis of 1-Fluoroalkoxyisoquinolines; General Procedure

In a reaction vial equipped with a magnetic stir bar, 1-chloroisoquinoline 7a (0.2 mmol) in HFIP (400 μL, 0.5 molar solution) was added. The reaction mixture was then stirred at 120 °C for 24 h on a heating mantle. After 24 h, the reaction was cooled to r.t., and the organic solvents were removed under reduced pressure. The residue was then diluted with a saturated solution of NaHCO₃ to neutralize the reaction mixture. The neutralized solution was extracted with EtOAc and collected in a round-bottom flask for the purification process. The organic solvent containing mixture was purified by column chromatography on silica gel (mesh 230–400) to give the desired product. Eluting solvents for chromatography are indicated under the specific compound headings.

Synthesis of 2-((1,1,1,3,3,3-Hexafluoropropan-2-yl)oxy)-1H-benzo[d]imidazole (10a); Typical Procedure

In a reaction vial equipped with magnetic stir bar, 2-chlorobenzamide 9a (0.2 mmol) in HFIP (400 μL, 0.5 molar solution) was added. The reaction mixture was then stirred at 120 °C for 24 h on a heating mantle. After 24 h, the reaction was cooled to r.t., and the organic solvents were removed under reduced pressure. The residue was then diluted with a saturated solution of NaHCO₃ to neutralize the acid produced during the reaction. The neutralized solution was extracted with EtOAc and collected in a round-bottom flask for the purification process. The organic solvent containing mixture was purified by column chromatography on silica gel (mesh 230–400) to give the desired product. Eluting solvents for chromatography are indicated under the specific compound headings.

4-((1,1,1,3,3,3-Hexafluoropropan-2-yl)oxy)quinoline (3a)

Isolated by column chromatography (30% EtOAc/n-hexane).

Yield: 56.1 mg (95%); white solid; mp 73–75 °C.

¹H NMR (600 MHz, CDCl₃): δ = 8.84 (d, J = 5.4 Hz, 1 H), 8.23 (dd, J = 8.4, 0.6 Hz, 1 H), 8.11 (d, J = 8.4 Hz, 1 H), 7.77–7.80 (m, 1 H), 7.60–7.63 (m, 1 H), 6.89 (d, J = 5.4 Hz, 1 H), 5.24–5.29 (m, 1 H).

¹³C{¹H} NMR (150 MHz, CDCl₃): δ = 159.7, 150.8, 149.9, 130.9, 129.3, 127.2, 120.9 (q, J _C–F = 284 Hz, 2 C), 121.5, 120.9, 102.0, 74.2 (hept, J _C–F = 35 Hz, 1 C).

¹⁹F NMR (565 MHz, CDCl₃): δ = –72.73 (s, 6 F).

IR (ZnSe): 3059, 2933, 1622, 1598, 1469, 1394, 1286, 1130, 1028, 904, 887, 717, 684 cm^–1.

HRMS (ESI-TOF): m/z [M + H]⁺ calcd for C₁₂H₈F₆NO: 296.0505; found: 296.0503.

4-((1,1,1,3,3,3-Hexafluoropropan-2-yl)oxy)-N-(4-methoxyphenyl)quinolin-2-amine (3c)

Isolated by column chromatography (20% EtOAc/n-hexane).

Yield: 24.9 mg (30%); white solid; mp 129–131 °C.

¹H NMR (600 MHz, CDCl₃): δ = 8.00 (d, J = 7.8 Hz, 1 H), 7.70 (d, J = 8.4 Hz, 1 H), 7.61–7.64 (m, 1 H), 7.35 (d, J = 9.0 Hz, 2 H), 7.30–7.32 (m, 1 H), 6.95 (d, J = 9.0 Hz, 2 H), 6.79 (s, 1 H, NH, 1 H), 6.33 (s, 1 H), 4.99–5.05 (m, 1 H), 3.85 (s, 3 H).

¹³C{¹H} NMR (150 MHz, CDCl₃): δ = 160.9, 157.1, 156.1, 149.3, 132.4, 131.4, 126.2, 124.7, 120.8 (q, J _C–F = 284 Hz, 2 C), 123.2, 121.6, 117.3, 114.9, 91.2, 73.9 (hept, J _C–F = 33 Hz, 1 C), 55.7.

¹⁹F NMR (565 MHz, CDCl₃): δ = –73.03 (s, 6 F).

IR (ZnSe): 2927, 2864, 1654, 1608, 1508, 1415, 1371, 1284, 1193, 1103, 1033, 912, 875, 721, 686 cm^–1.

HRMS (ESI-TOF): m/z [M + H]⁺ calcd for C₁₉H₁₅F₆N₂O₂: 417.1032; found: 417.1041.

4-((1,1,1,3,3,3-Hexafluoropropan-2-yl)oxy)-2-(4-methoxyphenyl)quinoline (3d)

Isolated by column chromatography (10% EtOAc/n-hexane).

Yield: 28.9 mg (36%); white solid; mp 100–102 °C.

¹H NMR (600 MHz, CDCl₃): δ = 8.20 (dd, J = 8.4, 0.6 Hz, 1 H), 8.14 (d, J = 8.4 Hz, 1 H), 8.07 (dd, J = 6.6, 1.8 Hz, 2 H), 7.76–7.78 (m, 1 H), 7.54–7.57 (m, 1 H), 7.27 (s, 1 H), 7.06 (dd, J = 7.8, 1.8 Hz, 2 H), 5.34 (sep, J = 5.4 Hz, 1 H), 3.89 (s, 3 H).

¹³C{¹H} NMR (150 MHz, CDCl₃): δ = 161.3, 160.4, 158.0, 149.9, 131.9, 131.0, 129.4, 129.0, 126.4, 121.01 (q, J _C–F = 284 Hz, 2 C), 121.3, 119.7, 114.5, 99.7, 74.4 (hept, J _C–F = 34 Hz, 1 C), 55.6.

¹⁹F NMR (565 MHz, CDCl₃): δ = –73.00 (s, 6 F).

IR (ZnSe): 2956, 2931, 1595, 1500, 1427, 1290, 1203, 1103, 1029, 918, 853, 759, 684 cm^–1.

HRMS (ESI-TOF): m/z [M + H]⁺ calcd for C₁₉H₁₄F₆NO₂: 402.0923; found: 402.0925.

4-((1,1,1,3,3,3-Hexafluoropropan-2-yl)oxy)-6-methylquinoline (3e)

Isolated by column chromatography (30% EtOAc/n-hexane).

Yield: 58.8 mg (95%); white solid; mp 110–113 °C.

¹H NMR (600 MHz, CD₃OD): δ = 9.13–9.15 (m, 1 H), 8.13–8.16 (m, 2 H), 8.02 (d, J = 9.0 Hz, 1 H), 7.85–7.87 (m, 1 H), 6.94–6.99 (m, 1 H), 2.66 (s, 3 H).

¹³C{¹H} NMR (150 MHz, CDCl₃): δ = 163.5, 146.3, 140.3, 140.1, 136.4, 122.6, 120.9, 120.70, 120.65 (q, J _C–F = 283 Hz, 2 C), 104.4, 73.7–74.8 (m, 1 C), 21.9.

¹⁹F NMR (565 MHz, CDCl₃): δ = –72.60 (s, 6 F).

IR (ZnSe): 3415, 3068, 2920, 1643, 1593, 1473, 1321, 1259, 1190, 1031, 906, 833, 761, 688 cm^–1.

HRMS (ESI–TOF): m/z [M + H]⁺ calcd for C₁₃H₁₀F₆NO: 310.0661; found: 310.0642.

6-Fluoro-4-((1,1,1,3,3,3-hexafluoropropan-2-yl)oxy)quinoline (3f)

Isolated by column chromatography (20% EtOAc/n-hexane).

Yield: 59.5 mg (95%); white solid; mp 58–60 °C.

¹H NMR (600 MHz, CDCl₃): δ = 8.80 (d, J = 4.8 Hz, 1 H), 8.10 (dd, J = 9.0, 5.4 Hz, 1 H), 7.80 (dd, J = 9.0, 3.0 Hz, 1 H), 7.52–7.55 (m, 1 H), 6.92 (d, J = 4.8 Hz, 1 H), 5.25 (hept, J = 5.4 Hz, 1 H).

¹³C{¹H} NMR (150 MHz, CDCl₃): δ = 160.93 (d, J = 249 Hz, 1 C), 159.3 (d, J _C–F = 6 Hz, 1 C), 150.0 (d, J _C–F = 2 Hz, 1 C), 147.1, 132.0 (d, J _C–F = 9 Hz, 1 C), 121.7 (d, J _C–F = 11 Hz, 1 C), 121.2 (d, J _C–F = 26 Hz, 1 C), 120.8 (q, J _C–F = 283 Hz, 2 C), 105.4 (d, J _C–F = 24 Hz, 1 C), 102.6, 74.2 (hept, J _C–F = 35 Hz, 1 C).

¹⁹F NMR (565 MHz, CDCl₃): δ = –73.12 (s, 6 F), –111.36 (s, 1 F).

IR (ZnSe): 2924, 1606, 1573, 1508, 1469, 1367, 1315, 1284, 1101, 1024, 908, 869, 759, 686 cm^–1.

HRMS (ESI–TOF): m/z [M + H]⁺ calcd for C₁₂H₇F₇NO: 314.0410; found: 314.0391.

6-Chloro-4-((1,1,1,3,3,3-hexafluoropropan-2-yl)oxy)quinoline (3g)

Isolated by column chromatography (20% EtOAc/n-hexane).

Yield: 61.3 mg (93%); white solid; mp 124–126 °C.

¹H NMR (600 MHz, CDCl₃): δ = 8.83 (d, J = 5.4 Hz, 1 H), 8.17 (d, J = 2.4 Hz, 1 H), 8.04 (d, J = 9.0 Hz, 1 H), 7.71 (dd, J = 9.0, 2.4 Hz, 1 H), 6.91 (d, J = 5.4 Hz, 1 H), 5.24 (hept, J = 5.4 Hz, 1 H).

¹³C{¹H} NMR (150 MHz, CDCl₃): δ = 158.8, 150.9, 148.4, 133.3, 131.9, 131.0, 121.7, 120.8 (q, J _C–F = 283 Hz, 2 C), 120.6, 102.6, 74.1 (hept, J _C–F = 34 Hz, 1 C).

¹⁹F NMR (565 MHz, CDCl₃): δ = –73.03 (s, 6 F).

IR (ZnSe): 2953, 1595, 1498, 1458, 1355, 1292, 1197, 1105, 1028, 910, 831, 758, 686 cm^–1.

HRMS (ESI–TOF): m/z [M + H]⁺ calcd for C₁₂H₇ClF₆NO: 330.0115; found: 330.0092.

6-Bromo-4-((1,1,1,3,3,3-hexafluoropropan-2-yl)oxy)quinoline (3h)

Isolated by column chromatography (20% EtOAc/n-hexane).

Yield: 74.1 mg (99%); white solid; mp 136–138 °C.

¹H NMR (600 MHz, CDCl₃): δ = 8.83 (d, J = 5.4 Hz, 1 H), 8.33 (d, J = 1.8 Hz, 1 H), 7.96 (d, J = 9.0 Hz, 1 H), 7.83 (dd, J = 9.0, 1.8 Hz, 1 H), 6.90 (d, J = 5.4 Hz, 1 H), 5.26 (hept, J = 5.4 Hz, 1 H).

¹³C{¹H} NMR (150 MHz, CDCl₃): δ = 158.6, 151.0, 148.5, 134.5, 131.0, 123.8, 121.9, 121.7, 120.8 (q, J _C–F = 282 Hz, 2 C), 102.6, 73.9 (hept, J _C–F = 34 Hz, 1 C).

¹⁹F NMR (565 MHz, CDCl₃): δ = –73.03 (s, 6 F).

IR (ZnSe): 3105, 3047, 2937, 1593, 1566, 1496, 1371, 1292, 1195, 1026, 910, 831, 758, 688 cm^–1.

HRMS (ESI-TOF): m/z [M + H]⁺ calcd for C₁₂H₇BrF₆NO: 373.9610; found: 373.9612.

4-((1,1,1,3,3,3-Hexafluoropropan-2-yl)oxy)-7-(trifluoromethyl)quinoline (3i)

Isolated by column chromatography (20% EtOAc/n-hexane).

Yield: 58.1 mg (80%); white crystalline solid; mp 78–80 °C.

¹H NMR (600 MHz, CDCl₃): δ = 8.96 (d, J = 4.8 Hz, 1 H), 8.42 (s, 1 H), 8.36 (d, J = 9.0 Hz, 1 H), 7.78–7.79 (m, 1 H), 7.02 (d, J = 4.8 Hz, 1 H), 5.25–5.31 (m, 1 H).

¹³C{¹H} NMR (150 MHz, CDCl₃): δ = 159.6, 152.2, 149.0, 132.9 (q, J _C–F = 33 Hz, 1 C), 127.1 (q, J _C–F = 4 Hz, 1 C), 124.7, 120.8 (q, J _C–F = 281 Hz, 2 C), 123.1, 122.94 (q, 3 Hz, 1 C), 122.90, 103.6, 74.3 (hept, J _C–F = 33 Hz, 1 C).

¹⁹F NMR (565 MHz, CDCl₃): δ = –63.02 (s, 3 F), –73.10 (s, 6 F).

IR (ZnSe): 2954, 1608, 1573, 1463, 1382, 1313, 1265, 1192, 1124, 1064, 902, 852, 738, 684 cm^–1.

HRMS (ESI-TOF): m/z [M + H]⁺ calcd for C₁₃H₇F₉NO: 364.0378; found: 364.0383.

7-Chloro-4-((1,1,1,3,3,3-hexafluoropropan-2-yl)oxy)quinoline (3j)

Isolated by column chromatography (20% EtOAc/n-hexane).

Yield: 60.6 mg (95%); brown solid; mp 103–105 °C.

¹H NMR (600 MHz, CDCl₃): δ = 8.84 (d, J = 5.4 Hz, 1 H), 8.15 (d, J = 9.0 Hz, 1 H), 8.10 (d, J = 1.8 Hz, 1 H), 7.55 (dd, J = 9.0, 1.8 Hz, 1 H), 6.89 (d, J = 5.4 Hz, 1 H), 5.24 (hept, J = 5.4 Hz, 1 H).

¹³C{¹H} NMR (150 MHz, CDCl₃): δ = 159.7, 152.0, 150.4, 137.1, 128.4, 128.2, 122.9, 120.8 (q, J _C–F = 282 Hz, 2 C), 119.4, 102.3, 74.2 (hept, J _C–F = 34 Hz, 1 C).

¹⁹F NMR (565 MHz, CDCl₃): δ = –73.11 (s, 6 F).

IR (ZnSe): 2951, 1618, 1566, 1498, 1427, 1317, 1261, 1128, 1089, 906, 877, 759, 686 cm^–1.

HRMS (ESI–TOF): m/z [M + H]⁺ calcd for C₁₂H₇ClF₆NO: 330.0115; found: 330.0112.

4-((1,1,1,3,3,3-Hexafluoropropan-2-yl)oxy)-6,7-dimethoxyquinoline (3k)

Isolated by column chromatography (50% EtOAc/n-hexane).

Yield: 39.1 mg (55%); viscous liquid.

¹H NMR (600 MHz, CDCl₃): δ = 8.62 (d, J = 5.4 Hz, 1 H), 7.40 (s, 1 H), 7.36 (s, 1 H), 6.79 (d, J = 5.4 Hz, 1 H), 5.20–5.25 (m, 1 H), 4.01 (s, 3 H), 4.01 (s, 3 H).

¹³C{¹H} NMR (150 MHz, CDCl₃): δ = 158.6, 153.4, 150.2, 148.6, 147.3, 121.0 (q, J _C–F = 283 Hz, 2 C), 115.9, 107.9, 101.4, 98.9, 74.5 (hept, J _C–F = 34 Hz, 1 C), 56.3, 56.1.

¹⁹F NMR (565 MHz, CDCl₃): δ = –73.27 (s, 6 F).

IR (ZnSe): 2968, 2926, 2845, 1624, 1579, 1479, 1392, 1350, 1246, 1109, 1035, 985, 860, 748, 688 cm^–1.

HRMS (ESI-TOF): m/z [M + H]⁺ calcd for C₁₄H₁₂F₆NO₃: 356.0716; found: 356.0726.

6-Chloro-4-((1,1,1,3,3,3-hexafluoropropan-2-yl)oxy)-2-methylquinoline (3l)

Isolated by column chromatography (20% EtOAc/n-hexane).

Yield: 61.9 mg (90%); white solid; mp 58–60 °C.

¹H NMR (600 MHz, CDCl₃): δ = 8.10 (d, J = 1.8 Hz, 1 H), 7.97 (d, J = 8.4 Hz, 1 H), 7.68 (dd, J = 9.0, 1.8 Hz, 1 H), 6.79 (s, 1 H), 5.23 (hept, J = 5.4 Hz, 1 H), 2.75 (s, 3 H).

¹³C{¹H} NMR (150 MHz, CDCl₃): δ = 160.2, 158.9, 147.9, 132.3, 131.8, 130.2, 120.8 (q, J _C–F = 283 Hz, 2 C), 120.4, 120.0, 103.3, 74.0 (hept, J _C–F = 34 Hz, 1 C), 25.9.

¹⁹F NMR (565 MHz, CDCl₃): δ = –73.01 (s, 6 F).

IR (ZnSe): 3020, 1620, 1600, 1556, 1492, 1342, 1286, 1232, 1105, 1076, 977, 744, 688 cm^–1.

HRMS (ESI–TOF): m/z [M + H]⁺ calcd for C₁₃H₉ClF₆NO: 344.0271; found: 344.0272.

9-((1,1,1,3,3,3-Hexafluoropropan-2-yl)oxy)acridine (3m)

Isolated by column chromatography (20% EtOAc/n-hexane).

Yield: 41.4 mg (60%); yellow solid; mp 144–146 °C.

¹H NMR (600 MHz, CDCl₃): δ = 8.24–8.26 (m, 4 H), 7.80–7.82 (m, 2 H), 7.60–7.62 (m, 2 H), 5.38 (hept, J = 5.4 Hz, 1 H).

¹³C{¹H} NMR (150 MHz, CDCl₃): δ = 155.9, 150.4, 130.7, 130.3, 126.8, 121.2 (q, J _C–F = 296 Hz, 2 C), 120.9, 118.7, 77.4 (hept, J _C–F = 24 Hz, 1 C).

¹⁹F NMR (565 MHz, CDCl₃): δ = –73.01 (s, 6 F).

IR (ZnSe): 2912, 1631, 1556, 1406, 1350, 1276, 1178, 1159, 1101, 1028, 933, 854, 740, 686 cm^–1.

HRMS (ESI-TOF): m/z [M + H]⁺ calcd for C₁₆H₁₀F₆NO: 346.0661; found: 346.0664.

4-(2,2,2-Trifluoroethoxy)quinoline (4a)[9]

Isolated by column chromatography (60% EtOAc/n-hexane).

Yield: 43.1 mg (95%); white solid; mp 88–90 °C.

¹H NMR (600 MHz, CDCl₃): δ = 8.79 (d, J = 5.4 Hz, 1 H), 8.23 (dd, J = 8.4, 1.2 Hz, 1 H), 8.07 (d, J = 8.4 Hz, 1 H), 7.73–7.76 (m, 1 H), 7.55–7.58 (m, 1 H), 6.70 (d, J = 5.4 Hz, 1 H), 4.58 (q, J = 7.8 Hz, 2 H).

¹³C{¹H} NMR (150 MHz, CDCl₃): δ = 159.9, 151.1, 149.6, 130.5, 129.2, 126.5, 123.1 (q, J _C–F = 276 Hz, 1 C), 121.7, 120.9, 100.7, 65.5 (q, J _C–F = 30 Hz, 1 C).

¹⁹F NMR (565 MHz, CDCl₃): δ = –73.51 (s, 4 F).

IR (ZnSe): 3053, 3005, 1622, 1573, 1508, 1448, 1396, 1321, 1284, 1159, 1078, 968, 881, 759, 665 cm^–1.

HRMS (ESI-TOF): m/z [M + H]⁺ calcd for C₁₁H₉F₃NO: 228.0631; found: 228.0630.

2-((1,1,1,3,3,3-Hexafluoropropan-2-yl)oxy)quinoline (6a)[7]

Isolated by column chromatography (10% EtOAc/n-hexane).

Yield: 41.9 mg (71%); white solid; mp 83–85 °C.

¹H NMR (600 MHz, CDCl₃): δ = 8.16 (d, J = 9.0 Hz, 1 H), 7.88 (d, J = 8.4 Hz, 1 H), 7.79–7.81 (m, 1 H), 7.69–7.72 (m, 1 H), 7.48–7.50 (m, 1 H), 7.09 (d, J = 9.0 Hz, 1 H), 6.87–6.93 (m, 1 H).

¹³C{¹H} NMR (150 MHz, CDCl₃): δ = 158.2, 145.2, 140.8, 130.5, 127.70, 127.66, 126.4, 125.7, 121.4 (q, J _C–F = 283 Hz, 2 C), 111.9, 67.3 (hept, J _C–F = 34 Hz, 1 C).

IR (ZnSe): 2960, 1618, 1510, 1427, 1340, 1220, 1193, 1091, 975, 810, 752, 686 cm^–1.

HRMS (ESI-TOF) (m/z): [M + H]⁺ calcd for C₁₂H₈F₆NO, 296.0505; found, 296.0507.

2-((1,1,1,3,3,3-hexafluoropropan-2-yl)oxy)quinoline-3-carbaldehyde (6b)

Isolated by column chromatography (10% EtOAc/n-hexane).

Yield: 17.4 mg (27%); white solid; mp 117–119 °C.

¹H NMR (600 MHz, CDCl₃): δ = 10.51 (s, 1 H), 8.76–8.77 (m, 1 H), 7.94–7.95 (m, 1 H), 7.92 (d, J = 9.0 Hz, 1 H), 7.82–7.84 (m, 1 H), 7.55–7.58 (m, 1 H), 6.94–6.99 (m, 1 H).

¹³C{¹H} NMR (150 MHz, CDCl₃): δ = 187.2, 157.1, 147.4, 141.5, 133.6, 130.0, 127.6, 126.8, 125.9, 121.1 (q, J _C–F = 282 Hz, 2 C), 119.4, 67.7 (hept, J _C–F = 34 Hz, 1 C).

¹⁹F NMR (565 MHz, CDCl₃): δ = –73.09 (s, 6 F).

IR (ZnSe): 2966, 2881, 1701, 1577, 1506, 1463, 1381, 1340, 1282, 1190, 1099, 931, 867, 761, 684 cm^–1.

HRMS (ESI-TOF): m/z [M + H]⁺ calcd for C₁₃H₈F₆NO₂: 324.0454; found: 324.0457.

4-Chloro-2-((1,1,1,3,3,3-hexafluoropropan-2-yl)oxy)quinoline (6c)

Isolated by column chromatography (10% EtOAc/n-hexane).

Yield: 35.5 mg (54%); viscous compound.

¹H NMR (600 MHz, CDCl₃): δ = 8.24 (d, J = 8.4 Hz, 1 H), 7.97 (d, J = 8.4 Hz, 1 H), 7.82–7.85 (m, 1 H), 7.65–7.68 (m, 1 H), 7.41 (s, 1 H), 7.10–7.16 (m, 1 H).

¹³C{¹H} NMR (150 MHz, CDCl₃): δ = 157.8, 146.0, 145.6, 131.5, 128.0, 126.6, 124.7, 124.4, 121.2 (q, J _C–F = 282 Hz, 2 C), 111.9, 67.7 (hept, J _C–F = 34 Hz, 1 C).

¹⁹F NMR (565 MHz, CDCl₃): δ = –73.13 (s, 6 F).

IR (ZnSe): 2922, 2852, 1967, 1257, 1226, 1093, 1055, 1022, 995, 806, 611 cm^–1.

HRMS (ESI-TOF): m/z [M + H]⁺ calcd for C₁₂H₇ClF₆NO: 330.0115; found: 330.0115.

1-((1,1,1,3,3,3-Hexafluoropropan-2-yl)oxy)isoquinoline (8a)[7]

Isolated by column chromatography (10% EtOAc/n-hexane).

Yield: 55.5 mg (94%); liquid compound.

¹H NMR (600 MHz, CDCl₃): δ = 8.31 (d, J = 8.4 Hz, 1 H), 7.99 (d, J = 5.4 Hz, 1 H), 7.82 (d, J = 8.4 Hz, 1 H), 7.73–7.76 (m, 1 H), 7.63–7.65 (m, 1 H), 7.41 (d, J = 6.0 Hz, 1 H), 6.85–6.91 (m, 1 H).

¹³C{¹H} NMR (150 MHz, CDCl₃): δ = 156.8, 138.8, 138.4, 131.5, 127.8, 126.5, 121.4 (q, J _C–F = 282 Hz, 2 C), 123.7, 118.9, 118.1, 67.8 (hept, J _C–F = 34 Hz, 1 C).

¹⁹F NMR (565 MHz, CDCl₃): δ = –73.26 (s, 6 F).

IR (ZnSe): 2980, 1635, 1577, 1502, 1479, 1438, 1375, 1352, 1261, 1180, 1080, 906, 817, 748, 688 cm^–1.

HRMS (ESI-TOF): m/z [M + H]⁺ calcd for C₁₂H₈F₆NO: 296.0505; found: 296.0502.

7-Chloro-1-((1,1,1,3,3,3-hexafluoropropan-2-yl)oxy)-4-methoxyisoquinoline (8b)

Isolated by column chromatography (10% EtOAc/n-hexane).

Yield: 14.4 mg (20%); white solid; mp 130–132 °C.

¹H NMR (600 MHz, CDCl₃): δ = 8.18 (d, J = 2.4 Hz, 1 H), 8.11 (d, J = 9.0 Hz, 1 H), 7.69 (dd, J = 9.0, 1.8 Hz, 1 H), 7.46 (s, 1 H), 6.67–6.73 (m, 1 H), 4.02 (s, 3 H).

¹³C{¹H} NMR (150 MHz, CDCl₃): δ = 149.5, 148.4, 146.6, 134.4, 131.8, 129.7, 123.7, 122.9 (q, J _C–F = 284 Hz, 2 C), 122.6, 119.7, 67.9 (m, 1 C), 56.3.

¹⁹F NMR (565 MHz, CDCl₃): δ = –73.24 (s, 6 F).

IR (ZnSe): 3089, 1575, 1498, 1379, 1292, 1261, 1172, 995, 831, 721, 640 cm^–1.

HRMS (ESI–TOF): m/z [M + H]⁺ calcd for C₁₃H₉ClF₆NO₂; 360.0221; found: 360.0195.

2-((1,1,1,3,3,3-Hexafluoropropan-2-yl)oxy)-1H-benzo[d]imidazole (10a)

Isolated by column chromatography (20% EtOAc/n-hexane).

Yield: 37.5 mg (66%); white solid; mp 151–153°C.

¹H NMR (600 MHz, CDCl₃): δ = 7.57 (d, J = 7.8 Hz, 1 H), 7.29–7.30 (m, 1 H), 7.21–7.25 (m, 2 H), 6.30–6.36 (m, 1 H).

¹³C{¹H} NMR (150 MHz, CDCl₃): δ = 154.9, 139.6, 132.3, 123.0, 122.9, 120.6 (q, J _C–F = 284 Hz, 2 C), 118.7, 110.5, 72.5 (hept, J _C–F = 36 Hz, 1 C).

¹⁹F NMR (565 MHz, CDCl₃): δ = –73.58 (s, 6 F).

IR (ZnSe): 3068, 2964, 2233, 1633, 1525, 1456, 1371, 1282, 1197, 1103, 1047, 908, 875, 740, 686 cm^–1.

HRMS (ESI–TOF): m/z [M + H]⁺ calcd for C₁₀H₇F₆N₂O: 285.0457; found: 285.0438.

Conflict of Interest

The authors declare no conflict of interest.

Acknowledgment

Authors are grateful to the Director, CSIR–IHBT for continuous encouragement. CSIR-IHBT communication no. for this manuscript is 4860.

• References

• 1a Conn HL, Luchi RJ. Am. J. Med. 1964; 37: 685
  CrossrefPubMedSearch in Google Scholar
• 1b Vasquez Vivar J, Augusto O. J. Biol. Chem. 1992; 267: 6848
  CrossrefPubMedSearch in Google Scholar
• 1c Chen YL, Fang KC, Sheu JY, Hsu SL, Tzeng CC. J. Med. Chem. 2001; 44: 2374
  CrossrefPubMedSearch in Google Scholar
• 1d Kumar S, Bawa S, Gupta H. Mini-Rev. Med. Chem. 2010; 9: 1648
  CrossrefSearch in Google Scholar
• 1e Bawa S, Kumar S, Drabu S, Kumar R. J. Pharm. Bioallied Sci. 2010; 2: 64
  CrossrefPubMedSearch in Google Scholar
• 1f Achan J, Talisuna AO, Erhart A, Yeka A, Tibenderana JK, Baliraine FN, Rosenthal PJ, D’Alessandro U. Malar. J. 2011; 10: 144
  CrossrefPubMedSearch in Google Scholar
• 1g Keri RS, Patil SA. Biomed. Pharmacother. 2014; 68: 1161
  CrossrefPubMedSearch in Google Scholar
• 1h Shang XF, Morris-Natschke SL, Liu YQ, Guo X, Xu XS, Goto M, Li JC, Yang GZ, Lee KH. Med. Res. Rev. 2018; 38: 775
  CrossrefPubMedSearch in Google Scholar
• 2 Wildman SA, Crippen GM. J. Chem. Inf. Comput. Sci. 1999; 39: 868
  CrossrefPubMedSearch in Google Scholar
• 3 van Niel MB, Collins I, Beer MS, Broughton HB, Cheng SK, Goodacre SC, Heald A, Locker KL, MacLeod AM, Morrison D, Moyes CR. J. Med. Chem. 1999; 42: 2087
  CrossrefPubMedSearch in Google Scholar
• 4a Barnette WE, Nicolaou KC. Crit. Rev. Biochem. 1984; 15: 201
  Search in Google Scholar
• 4b Clader JW. J. Med. Chem. 2004; 47: 1
  CrossrefPubMedSearch in Google Scholar
• 5a O’Neill PM, Storr RC, Park BK. Tetrahedron 1998; 54: 4615
  CrossrefSearch in Google Scholar
• 5b Crockett M, Kain KC. Expert Opin. Invest. Drugs 2007; 16: 705
  CrossrefPubMedSearch in Google Scholar
• 5c Müller K, Faeh C, Diederich F. Science 2007; 317: 1881
  CrossrefPubMedSearch in Google Scholar
• 5d Hird M. Chem. Soc. Rev. 2007; 36: 2070
  CrossrefPubMedSearch in Google Scholar
• 5e Purser S, Moore PR, Swallow S, Gouverneur V. Chem. Soc. Rev. 2008; 37: 320
  CrossrefPubMedSearch in Google Scholar
• 5f Wang J, Sánchez-Roselló M, Aceña JL, Del Pozo C, Sorochinsky AE, Fustero S, Liu H. Chem. Rev. 2014; 114: 2432
  CrossrefPubMedSearch in Google Scholar
• 6 Stephens DE, Chavez G, Valdes M, Dovalina M, Arman HD, Larionov OV. Org. Biomol. Chem. 2014; 12: 6190
  CrossrefPubMedSearch in Google Scholar
• 7 Zhang D, Qiao K, Hua J, Liu Z, Qi H, Yang Z, Zhu N, Fang Z, Guo K. Org. Chem. Front. 2018; 15: 2340
  CrossrefPubMedSearch in Google Scholar
• 8 Iwai T, Sawamura M. ACS Catal. 2015; 5: 5031
  CrossrefSearch in Google Scholar
• 9 Pethő B, Zwillinger M, Csenki J, Káncz A, Krámos B, Müller J, Balogh GT, Novák Z. Chem. Eur. J. 2017; 23: 15628
  CrossrefPubMedSearch in Google Scholar
• 10 Shen X, Neumann CN, Kleinlein C, Goldberg NW, Ritter T. Angew. Chem. Int. Ed. 2015; 54: 5662
  CrossrefPubMedSearch in Google Scholar
• 11a Sinha SK, Bhattacharya T, Maiti D. React. Chem. Eng. 2019; 4: 1492
  CrossrefSearch in Google Scholar
• 11b Bhattacharya T, Ghosh A, Maiti D. Chem. Sci. 2021; 12: 3857
  CrossrefPubMedSearch in Google Scholar
• 12 Chen L, Chen S, Michoud C. US 2006/0004046 Al, 2006
• 13a Rohrbach S, Smith AJ, Pang JH, Poole DL, Tuttle T, Chiba S, Murphy JA. Angew. Chem. Int. Ed. 2019; 58: 16368
  CrossrefPubMedSearch in Google Scholar
• 13b Ando S, Tsuzaki M, Ishizuka T. J. Org. Chem. 2020; 85: 11181
  CrossrefPubMedSearch in Google Scholar

Corresponding Author

Publication History

Received: 12 May 2021

Accepted after revision: 17 June 2021

Accepted Manuscript online:
17 June 2021

Article published online:
20 July 2021

© 2021. Thieme. All rights reserved

Georg Thieme Verlag KG
Rüdigerstraße 14, 70469 Stuttgart, Germany

• References

• 1a Conn HL, Luchi RJ. Am. J. Med. 1964; 37: 685
  CrossrefPubMedSearch in Google Scholar
• 1b Vasquez Vivar J, Augusto O. J. Biol. Chem. 1992; 267: 6848
  CrossrefPubMedSearch in Google Scholar
• 1c Chen YL, Fang KC, Sheu JY, Hsu SL, Tzeng CC. J. Med. Chem. 2001; 44: 2374
  CrossrefPubMedSearch in Google Scholar
• 1d Kumar S, Bawa S, Gupta H. Mini-Rev. Med. Chem. 2010; 9: 1648
  CrossrefSearch in Google Scholar
• 1e Bawa S, Kumar S, Drabu S, Kumar R. J. Pharm. Bioallied Sci. 2010; 2: 64
  CrossrefPubMedSearch in Google Scholar
• 1f Achan J, Talisuna AO, Erhart A, Yeka A, Tibenderana JK, Baliraine FN, Rosenthal PJ, D’Alessandro U. Malar. J. 2011; 10: 144
  CrossrefPubMedSearch in Google Scholar
• 1g Keri RS, Patil SA. Biomed. Pharmacother. 2014; 68: 1161
  CrossrefPubMedSearch in Google Scholar
• 1h Shang XF, Morris-Natschke SL, Liu YQ, Guo X, Xu XS, Goto M, Li JC, Yang GZ, Lee KH. Med. Res. Rev. 2018; 38: 775
  CrossrefPubMedSearch in Google Scholar
• 2 Wildman SA, Crippen GM. J. Chem. Inf. Comput. Sci. 1999; 39: 868
  CrossrefPubMedSearch in Google Scholar
• 3 van Niel MB, Collins I, Beer MS, Broughton HB, Cheng SK, Goodacre SC, Heald A, Locker KL, MacLeod AM, Morrison D, Moyes CR. J. Med. Chem. 1999; 42: 2087
  CrossrefPubMedSearch in Google Scholar
• 4a Barnette WE, Nicolaou KC. Crit. Rev. Biochem. 1984; 15: 201
  Search in Google Scholar
• 4b Clader JW. J. Med. Chem. 2004; 47: 1
  CrossrefPubMedSearch in Google Scholar
• 5a O’Neill PM, Storr RC, Park BK. Tetrahedron 1998; 54: 4615
  CrossrefSearch in Google Scholar
• 5b Crockett M, Kain KC. Expert Opin. Invest. Drugs 2007; 16: 705
  CrossrefPubMedSearch in Google Scholar
• 5c Müller K, Faeh C, Diederich F. Science 2007; 317: 1881
  CrossrefPubMedSearch in Google Scholar
• 5d Hird M. Chem. Soc. Rev. 2007; 36: 2070
  CrossrefPubMedSearch in Google Scholar
• 5e Purser S, Moore PR, Swallow S, Gouverneur V. Chem. Soc. Rev. 2008; 37: 320
  CrossrefPubMedSearch in Google Scholar
• 5f Wang J, Sánchez-Roselló M, Aceña JL, Del Pozo C, Sorochinsky AE, Fustero S, Liu H. Chem. Rev. 2014; 114: 2432
  CrossrefPubMedSearch in Google Scholar
• 6 Stephens DE, Chavez G, Valdes M, Dovalina M, Arman HD, Larionov OV. Org. Biomol. Chem. 2014; 12: 6190
  CrossrefPubMedSearch in Google Scholar
• 7 Zhang D, Qiao K, Hua J, Liu Z, Qi H, Yang Z, Zhu N, Fang Z, Guo K. Org. Chem. Front. 2018; 15: 2340
  CrossrefPubMedSearch in Google Scholar
• 8 Iwai T, Sawamura M. ACS Catal. 2015; 5: 5031
  CrossrefSearch in Google Scholar
• 9 Pethő B, Zwillinger M, Csenki J, Káncz A, Krámos B, Müller J, Balogh GT, Novák Z. Chem. Eur. J. 2017; 23: 15628
  CrossrefPubMedSearch in Google Scholar
• 10 Shen X, Neumann CN, Kleinlein C, Goldberg NW, Ritter T. Angew. Chem. Int. Ed. 2015; 54: 5662
  CrossrefPubMedSearch in Google Scholar
• 11a Sinha SK, Bhattacharya T, Maiti D. React. Chem. Eng. 2019; 4: 1492
  CrossrefSearch in Google Scholar
• 11b Bhattacharya T, Ghosh A, Maiti D. Chem. Sci. 2021; 12: 3857
  CrossrefPubMedSearch in Google Scholar
• 12 Chen L, Chen S, Michoud C. US 2006/0004046 Al, 2006
• 13a Rohrbach S, Smith AJ, Pang JH, Poole DL, Tuttle T, Chiba S, Murphy JA. Angew. Chem. Int. Ed. 2019; 58: 16368
  CrossrefPubMedSearch in Google Scholar
• 13b Ando S, Tsuzaki M, Ishizuka T. J. Org. Chem. 2020; 85: 11181
  CrossrefPubMedSearch in Google Scholar

• Supplementary Material
• Primary Data